1. ASCO 2005 Adjuvant Breast Cancer Update
Lori J. Goldstein, MD
Director, Breast Evaluation Center
Leader, Breast Cancer Research Program
Fox Chase Cancer Center
Philadelphia, PA

2. ASCO 2005 Breast Cancer Update
Abstract #/ Session Title/ Subject
E2197: Adjuvant AT vs. AC
ECTO: A->CMF vs AT->CMF
MoAB Ed N9831/ NSABP B31 Joint Analysis – Adjuvant Trastuzumab
MoAB Ed N9831 – Adjuvant Trastuzumab
MoAB Ed HERA: Adjuvant Trastuzumab
MoAB Ed E2100: T +/- bevacizumab MBC

3. E2197: Phase III AT vs. AC in the Adjuvant Treatment of Node Positive and High Risk Node Negative Breast Cancer
Goldstein LJ, O’Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE.
On behalf of ECOG and the US Intergroup, thank you for allowing me to present the first results of E2197, a randomized trial comparing adriamycin plus docetaxel to adriamycin plus cyclophosphamide for node positive and hi risk node negative breast cancer.

4. E2197 Rationale Phase II Studies Anthracyline + Taxane
Study A/Por D mg/m2 RR % CHF %
Gianni/ 60/P
Dombernowsky
Sledge E /P
Sparano E /P
Sparano E /D
Cresta 60/D
Misset 50/D
Given their single agent activity, relative non-cross resistance, partially non-overalpping toxicities and different mechanisms of action, there was a clear rationale for combining the taxanes with doxorubicin. The encouraging results of the combination of doxorubicin and palcitaxel were associated with a risk of cardiac toxicity related to cumulative doxorubicin dose and alteration of doxorubicin pharmacokinetcs by paclitaxel which was highly sequence dependent
Here are some of the Phase II trial s in metastatic breast cancer. The combination of doxorubicin and docetaxel was selected for E2197 based on the relative cardiac safety of this combination.

5. E2197 Rationale Phase III Studies:Anthracyline + Docetaxel
MBC AT (50/75) AC (60/600)
RR% p=.012
TTPwk p=.015
CHF % 2 4
FN%
No difference OS Nabholtz JCO 2003
TAC vs. FAC MBC Mackey ASCO 2002
Increase RR with TAC; no difference in TTP or OS
TAC vs. FAC Adjuvant: Nabholtz ASCO 2002
TAC increase DFS/ OS
Subsequent to the initiation of E2197 several randomized trials were published supporting the investigation of this combination in the adjuvant treatment of early stage breast cancer.
Here one can see that AT resulted in an increased response rate and time to tumor progression compared to AC in metastatic breast cancer with a low incidence of CHF. As you can also see the AT combination is associated with significant febrile neutropenia when given without growth factor support.
These data are also supported by the comparison of TAC vs FAC. While TAC resulted in an increased response rate there was no improvement in time to progression when compared to FAC in metastatic breast cancer.
However, in the adjuvant setting, TAC was superior to FAC in terms of both disease free and overall survival.

6. E2197: Schema R A N D O M I Z E IV q 3wk x 4 Cipro 500mg
po. bid D8 x 10d
Adriamycin 60mg/m2
Docetaxel (T) 60mg/m2
T1-3 N0-1 M0
No then
T> 1.0cm
Adriamycin 60mg/m2
Cyclophosphamide 600mg/m2
IV q 3wk x 4
Tamoxifen 20mg daily x 5 years
post chemotherapy for ER and/or
PR positive tumor
Stratified:
Nodal Status
HR Status (ER+PR+,ER+PR-,
ER-PR+,ER- PR-,ER/PR unknown)
Menopausal Status
*G-CSF -
per ASCO guidelines

7. E2197: Objectives To determine whether AT will improve DFS and OS
To compare toxicity of AT vs. AC
No difference in LVEF between AT and AC reported ASCO 2003.
At ASCO 2003 we reported no difference in LVEF bewteen AT and AC.

8. E2197: Study Design
Primary endpoint: DFS-recurrences, new breast primaries, or death without recurrence whichever comes first.
Design: 83% power to detect a 25% reduction of the DFS failure hazard rate
(5% absolute improvement in 5 yr DFS from 78% to 83% by using AT)
Sample size: including an estimated 10% ineligible
Primary Analysis: Intent-to-treat analysis on eligible patients.
The primary endpoint was DFS defined a recurrence, new breast cancer, or death without recurrence.
With 2778 patients (inlcuding 10% ineligible) this study had 83% power to detect a 25% reduction in DFS hazard rate using AT
This was an intent to treat analysis.
__________________________________________________________________________________________________________________
(assuming a 5 yr 78% DFS on the AC arm OR
The ability to detect a 5% absolute improvement in 5 yr DFS from 78% to 83%.
2 interims and a final analysis planned (total information=420 DFS failures)
The information time was defined by the number of eligible patients who recur, have a new breast cancer primary or die without recurrence whichever occurred first.

9. E2197:Results Opened 7/30/98; closed 1/21/00
2952 entered through the collaborative effort of ECOG, CALGB, NCCTG, SWOG and EPP.
3% Ineligibility rate
2885 eligible and analyzable

10. E2197: Patient Characteristics
Balanced for age, HR, menopause, nodes, surgery, grade and size
Age range yo, Median age 51
64% ER +
65% LN-
Grade: 10% low, 38% int., 46% high
Size: 0.1 – 12.5 cm; Median – 2.0 cm
The arms were balanced for age, hormone receptors, menopause, nodes, surgery, grade and size.
The Age range was , with a Median age of 51
64% were ER +
65% were LN-
For Grade: 10% were low, 38% int., and 46% high
For Size:the range was 0.1 – 12.5 cm; with a Median size of 2.0 cm

11. E2197: Toxicity Summary AT AC Feb/Infxn/N 28% 10% AML/MDS 7 7
Lethal Events
Related 4
Unrelated
As noted in other studies of the AT combination, the neutropenia associated with fever and infection was significant at 28% compared to AC where the rate was 10%. Again noted is that growth factor was not given prophylactically, but rather by ASCO guidelines.
There were 7 cases of AML/MDS on each arm.
There were 7 deaths during or within 30 days of chemo and One death at 42 days.
4 were related to treatment with AT, one with visceral ishcemia( ischemic bowel), 2 secondary to sepsis and one cardiac in a patient with a cardiac history.
Ages 62-70).
AT Unrelated:
Cardiac – h/o cardiac disease (77)
Sudden death (60)
AC Unrealted
Angioedema of the larynx post endoscopy
MI post chemo

12. E2197 Cardiac Safety AT AC Grade 3 4 5 3 4 CHF 15 2 1 10 Total 18 10%
No statistically significant difference
There 18 and 10 cases of CHF on the AT and AC arms respectively, with no significant difference between the 2 arms.

13. E2197: DFS Fall 2004 DMC (409/ 420 DFS failures)
O’Brien-Fleming boundary had not been crossed, there was not enough evidence to suggest a significant difference
April Median follow-up = 59 months
432/ 2885 (15%) recurred, developed second breast cancer or died.
At the Fall 2004 DMC, the study was at full information and the ECOG DMC released the study for presentation and publication.
The current data are as of April 2005.
At 59 month median follow-up, 432 of 2885 patients recurred, developed second breast cancers or died.

14. E2197: DFS/OS Hazard Ratio HR > 1 favors AT HR (adjusted)
DFS ( ), p=0.70
OS ( ), p=0.49
As of 4/4/05, 242 deaths
With a Hazard ratio greater than 1 favoring AT there was no significant difference in disease free or overall survival between the 2 arms.
The Hazard ratio was adjusted for age, nodes, ER, menopausal status, surgery, grade, size. The unadjusted HR’s were not significantly different.

15. E2197 Disease-Free Survival
Percent 10 20 30 40 50 60 70 80 90
100
Months 12 24 36 48 72 AT AC
1444
213
1441
219 N
Events 87
(1)
4-Yr %
(S.E.)
E2197 Disease-Free Survival
The K-M curves are overlappiing for a disease free survival.
The 4 year DFS was 87% for both arms.

16. Percent 10 20 30 40 50 60 70 80 90
100
Months 12 24 36 48 72 AT AC
1444
117
1441
125 N
Events 94
(1) 93
4-Yr %
(S.E.)
E2197 Overall Survival
Similarly, the curves overlap for overall survival with 94% survival at 4yrs.

17. E2197: DFS Subgroup Analysis
No significant effect within any of the following subgroups :
Nodes
Size
Age
Menopausal Status
Grade
Type of Surgery
Race
No significant effect was observed within any of the following subgroups :
Nodes
Size
Age
Menopausal Status
Grade
Type of Surgery
Race
NB: There were no significant interactions between treatment and any of these variables.

18. E2197 Disease-Free Survival:ER-/PR- 10 20 30 40 50 60 70 80 90
100
100 90 80 70 60
Percent
Percent 50 40 30 20 10 12 24 36 48 60 72 12 24 36 48 60 72
Months
Months N
Events
4-Yr %
(S.E.) N
Events
4-Yr %
(S.E.) AT
454 85 83 83 83
(2)
(2)
(2) AT 52 14 77
(6) AC
463
109 79 79 79 79 79 79 79 79
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2) AC 38 3 95
(4)
E2197 Disease-Free Survival:ER+/PR-
E2197 Disease-Free Survival:ER+/PR+
100
100 90 90 80 80 70 70 60
The ER/PR subgroups were prespecified stratification groups at randomization designed to balance the treatment arms.
And are not powered to detect differences between the subgroups.
While there is no statistically significant difference in the ER+ and ER- tumors, these curves illustrate the 4 prespecified ER/PR subgroups.
In the ER-/PR- and the ER+/PR – seen on the left side of the slide, there were fewer events in the AT arm.
For the ER-/PR- group, the 4 yr DFS was 83% for AT and 79% for AC.
For the ER+/PR- group, the DFS was 90 % and 83% respectively for AT and AC, acknowledging that this subgroup is quite small.
On the top right, the ER-/PR+ subgroup was extremely small and may represent lab error for ER and therefore this curve could be collapsed into the ER+/PR+ curve below it showing no difference between the 2 arms, and this represents the majority of patients. 60
Percent 50
Percent 50 40 40 30 30 20 20 10 10 12 24 36 48 60 72 12 24 36 48 60 72
Months
Months N
Events
4-Yr %
(S.E.) N
Events
4-Yr %
(S.E.) AT
162 22 90
(2) AT
767 91 90 90 90 90 90 90 90
(1)
(1)
(1)
(1)
(1)
(1)
(1) AC
164 34 81 83 81
(3)
(3)
(3) AC
770 73 92 92 92 92 92 92 92
(1)
(1)
(1)
(1)
(1)
(1)
(1)

19. Disease Free Survival ER-/PR- 1.30 (0.96, 1.70) ER-/PR+
0.30 (0.10, 0.95)
ER+/PR-
1.64 (0.96, 2.80)
Here the same subgroup data are illustrated in this forest plot of DFS where anything to the right of 1 favors AT.
Again the largest group is the ER+/PR+ group with the very small ER-/PR+ group likely collapsing into it.
This again suggests that the PR – tumors may potentially benefit from AT but the study was not powered to statistically detect these differences.
The same pattern is seen for OS, data not shown.
These data support the hypothesis presented by Don Berry at San Antonio, that the in the ER positive tumors the large benefit provided by Tamoxifen, overwhelms the potential benefit to chemo, or that the prognosis of these tumors is so good it is difficult to detect a difference between the 2 chemotherapy arms.
Taken together along with the Genomic Health data, this data supports the hypothesis that the biology of the tumor may predict the benefit to individual therapies.
ER+/PR+
0.79 (0.58, 1.10)
0.1
0.2
0.5 1 2 5
Favors AC
Favors AT

20. E2197 Conclusions
These results show a better than expected outcome for both regimens.
87%(obs) vs 78% (expected for AC) DFS at 4 yrs.
At 59 mo median follow-up, there is no difference in DFS or OS between AT and AC.
Prespecified stratifications at randomization: LN, menopause, ER/PR – no significant difference between the 2 treatment arms.
In PR negative tumors, a potential benefit to AT may be suggested.
These results show a better than expected outcome for both regimens.
87%(obs) vs 78% (expected for AC) DFS at 4 yrs.
At 59 mo median follow-up, there is no difference in DFS or OS between AT and AC.
Prespecified stratifications at randomization: LN, menopause, ER/PR – no significant difference between the 2 treatment arms.
In PR negative tumors, a potential benefit to AT may be suggested.

21. E2197: Issues for Discussion
Would longer f/u change these results? Unlikely
Observed DFS = 87% at 4 yrs.
Expected DFS = 78% at 4yrs.
Aromatase Inhibitor Affect:
60% on Tam; Median 41 mo; AI info collected; future analysis
Subset analysis of prespecified ER/PR stratifications:
Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies.
Central review of ER/PR/Her 2 pending
Genomic Health/ Sanofi-Aventis Analysis:
Oncotype
Genomic profiling
Use as training set for validation with E1199
Pharmacogenomics
PACCT- 1 Trial
Would longer f/u change these results? Unlikely
Observed DFS = 87% at 4 yrs.
Expected DFS = 78% at 4yrs.
The better than anticipated DFS may represent the continued improved prognosis over time that we have observed in Intergroup trials.
In fact the predecessor to this trial, 9313, there was an 80% 5 yr DFS.
What about the Aromatase Inhibitor Affect:
60% started Tam; About half have finished; with a Median of 41 mo on tamoxifen; AI info collected since 2004 for future analysis
Subset analysis of prespecified ER/PR stratifications: lead to the
Hypothesize that the biology of the primary tumor predicts outcome and benefit to specific therapies.
Central review of ER/PR/Her 2 is ongoing
With support from Genomic Health and Sanofi-Aventis we will perform the following analyses
Oncotype
Genomic profiling
to Use these data as training set for validation with E1199
In addition to Pharmacogenomics
In addition, These data support the design of the PACCT –1 trial
Program for the assessment of clinical cancer tests – Phase III validation study of genomic profiling
Intergroup 9313 AC vs. A->C; at median f/u of 5.3 yrs,, the estimated 5 yr DFS was 80%.
Refer to NSABP studies of eight + years f/u to see differences in low risk population of tumors< 1 cm. B 13, 19, 14 and 20.
Fisher at al. JNCI 93(2): Jan 17, 2001
Prognosis and treatment of patient with breast tumors one cm or less and negative axillary nodes.
ER - = 235: surgery +/- ctx
ER + = 1024: surgery, tam +/- ctx
8yr RFS for ER -: Surgery = 81%; surgery + ctx = 90%; p=.06
Survival similar in both groups: 93 and 91%; p= .65.
8 yr RFS for ER+:
Surgery = 86%
Surgery/tam = 93%; p= .01
Surgery/tam/ctx = 95%; p= .07 compared with tam
Survival was 90%, 92% ( p=,41). and 97% respectively. P=.01 in the latter 2 groups.
Although the majority of tumor recurrences occur in the first decade of f/u, the proportion of recurrences that occur in the second decade of f/u increases in women with small tumors. Consequently a follow-up longer than 8 years is likely necessary to allow for a more meaningful assessment of the outcome of these patients. Mortality at 8 yrs f/up was 8% for t< 1 cm. I/2 of deaths were related to breast cancer. Therefore the findings in these patients with short follow-up should be viewed with caution.
Would longer follow-up change these results? Statistically no, even though the entire group did better that anticipated compared to historical controls.
PACCT-1 Program for the assessment of clinical cancer tests – Phase III validation study of genomic profiling

22. Anne O’Neill, Deborah Namande, Eric Ross
Thank You
Patients
Data managers/ CRA’s
CALGB, NCCTG, SWOG, EPP
Anne O’Neill, Deborah Namande, Eric Ross

23. European Cooperative Trial in Operable Breast Cancer(ECTO): Improved freedom from progression from adding paclitaxel(T) to doxorubicin(A) followed by CMF
Luca Gianni
Abstract 513

24. ECTO: Schema Tumors > 2 cm randomized to :
SURG ->A 75 mg/m2 x 4 -> CMF x 4
SURG ->AT 60/ 200 x 4 -> CMF x 4
AT 60/ 200 x 4 -> CMF x 4 -> SURG
Tam for HR +
Analysis: FFP A vs B
B vs C

25. ECTO at 5 years Analysis A vs. B
Pts. Events HR p
A-CMF *
AT-CMF
Analysis B vs. C
S-AT-CMF
AT-CMF-S
Data super imposable so far, no significant difference, however pCR had improved FFP.

26. ECTO: Main Treatment Outcomes
A(%) B(%) C(%)
Total FFP
pCR
no pCR N N
N +> OS
No significant difference in OS.
No significant difference in cardiac toxicity

27. Combined Analysis of NSABP-B31/NCCTG-N9831
Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer
Romond EH, Perez EA, Bryant J, Suman V, Geyer CE,
Davidson N, Tan-Chiu E, Martino S, Swain SM, Kaufman P, Fehrenbacher L, Pisansky T, Vogel V, Kutteh LA, Yothers G, Visscher D, Brown AM, Jenkins R, Seay TE, Mamounas E, Abrams J, Wolmark N
Combined Analysis of NSABP-B31/NCCTG-N9831

28. NSABP B-31 NCCTG N9831 Control: ACT Arm 1 Arm 2 Arm A Arm B Arm C
Investigational: ACT+H
Arm B
Arm C
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4
= paclitaxel (T) 175 mg/m2 q 3 wk x 4
= paclitaxel (T) 80 mg/m2/wk x 12
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

29. Patient Eligibility
HER-2 positive by FISH or +++ by IHC verified centrally (N9831) or by approved reference lab (B-31)
Normal left ventricular ejection fraction
No past or active cardiac disease including:
History of myocardial infarction
History of congestive heart failure
Angina pectoris requiring medication
Arrhythmia requiring medication
Clinically significant valvular disease
Uncontrolled hypertension
LVH
Cardiomegaly on CXR

30. LVEF Evaluation Schedule
B-31 Arm 2 / N9831 Arm C
AC Paclitaxel + Trastuzumab
mo. 3
mos. 6
mos. 9
mos. 18
mos.
B-31 Arm 1 / N9831 Arm A
AC Paclitaxel
mo. 3
mos. 6
mos. 9
mos. 18
mos.

31. Relationship of LVEF to LLN
Asymptomatic Patients Rules for Trastuzumab Continuation Based on Serial LVEFs
Relationship of LVEF to LLN
Absolute Decrease
of < 10%
Absolute Decrease
of %
Absolute Decrease
of  16%
Within Normal Limits
1- 5 % below LLN
 6 % below LLN
Cont.
Cont.*
Cont.
Hold *
Hold *
Once the patients start Herceptin, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Herceptin doses.
* Repeat LVEF assessment after 4 weeks
- If criteria for continuation met – resume trastuzumab
- If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab

32. B-31: Trastuzumab Discontinuation Due to Asymptomatic or Symptomatic
Cardiac Dysfunction by Quarter

33. Patient and Tumor Characteristics (%)
AC  Paclitaxel
+ Trastuzumab
872
B-31
807
N9831
864
808
Age
<50
50-59
≥60 52 34 15 51 32 16 50 18
No. Pos Nodes
1-3
4-9
10+ 57 29 14 13 48 25 11
Hormone Receptors
ER+
ER-
PR+
PR- 53 47 41 58 46 39 60
Tumor Size
≤2.0 cm.
cm.
>4.0 cm. 43 40 37 44 17 38

34. Statistical Analysis
Median follow-up: 2.0 years (2.4 years on B-31/1.5 years on N9831)
Primary endpoint: DFS
analyzed by intent-to-treat
Secondary endpoints: OS and Time to 1st Distant Recurrence
Definitive analysis after 710 DFS events
First interim analysis after 355 DFS events
Stop trials only if equivalence is rejected at p= (2p=0.001)

35. Disease-Free Survival
ACTH
87%
85%
ACT
75% %
67%
N Events
ACT
ACTH
HR=0.48, 2P=3x10-12
Years From Randomization
B31/N9831

36. Forest Plot For Disease-Free Survival
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone
Receptor
Positive
Negative
Tumor
Size
≥ 4.1cm cm
<2.0 cm
No.
Positive
Nodes
10+
4-9
1-3
Protocol
N9831
NSABP B-31
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Hazard Ratio

37. Disease-Free Survival1 2 3 4 5 50 60 70 80 90
100
B-31
N9831
ACTH
ACTH
87%
87%
85%
ACT
86%
ACT
78%
74% %
68%
66%
N Events
N Events
ACT
ACT
ACTH
ACTH
HR=0.55, 2P=0.0005
HR=0.45, 2P=1x10-9
Years From Randomization

38. Time to First Distant Recurrence
100
ACTH
AC->T+H
90%
90%
90%
90%
90%
90% 90
ACT
AC->T 80
81%
81%
81% %
74%
74% 70
74%
N Events
N Events
ACTH
ACT
AC->T 60
AC->T+H
HR=0.47, 2P=8x10-10
HR=0.47, 2P=8x10-10 50 1 2 3 4 5
Years From Randomization
B31/N9831

39. Hazard of Distant Recurrence
120
100
ACT 80
Rate per 1000 Women /Yr 60 40
ACTH 20 1 2 3 4
Years From Randomization
B31/N9831

40. B-31/N9831 Survival ACTH 94% 91% ACT 92% 87% N Deaths ACT 1679 92
HR=0.67, 2P=0.015
Years From Randomization
B31/N9831

42. B-31: Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF
P(Age)=0.04
P(LVEF)<0.0001

43. Conclusions
For high risk HER-2 positive breast cancer, trastuzumab given concurrently with paclitaxel following AC chemotherapy, reduces the risk of a first breast cancer event at 3 years by 52%.
The relative risk reduction benefit was present and of similar magnitude in all subsets of patients analyzed. There is not, however, statistical power to establish efficacy in the node negative subset.
The addition of trastuzumab reduced the probability of distant recurrence by 53% at 3 years, and the hazard of developing distant metastases appears, thus far, to decrease over time.

44. Conclusions
4. Results at a median follow-up of 2 years show a statistically significant survival advantage with a relative risk reduction of 33%.
5. The combination of trastuzumab and chemotherapy has a notable risk of cardiac toxicity. Careful monitoring of cardiac function is of vital importance if trastuzumab is to be used in the adjuvant setting.

45. Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P, on Behalf of
NCCTG N May 2005 Update
Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P, on Behalf of
NCCTG, ECOG, SWOG, CALGB

46. Radiation and/or hormonal therapy as indicated
NCCTG N9831 Schema
Paclitaxel qw x 12
Arm A:
AC q3w x 4
RANDOMI Z E
Arm B:
AC q3w x 4
Paclitaxel qw x 12
H qw x 52
Paclitaxel qw x 12 +
H qw x 12
Arm C:
H qw x 40
AC q3w x 4
Radiation and/or hormonal therapy as indicated
Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg); doxorubicin dose 60mg/m2; cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2
q3w=every 3 weeks; qw=weekly

47. Statistical Plan Addition of H to AC  T
Two pairwise comparisons
Goal
To detect a 33% increase in median DFS from 6.3 to 8.4 years
Final analysis
At 663 events for A vs C comparison
At 789 events for A vs B comparison
Sequential
AC  T  H vs
Control: AC  T
Concurrent
AC  T + H  H
Control: AC  T vs
T=paclitaxel; DFS=disease free survival

48. Statistical Plan Timing of H Initiation
Pairwise comparison
Goal
To detect a 29% increase in median DFS from 7.3 to 9.4 years
Final analysis
At 590 events for B vs C comparison
Sequential
AC  T  H
Concurrent
AC  T + H  H vs

49. No H if symptoms or LVEF ↓ >15% or ↓ to <LLN
Cardiac Testing
RANDOMI Z E 
Arm A: AC x 4
Paclitaxel  
Arm B: AC x 4
Paclitaxel H  
Arm C: AC x 4
Paclitaxel + H H
Time (months) 3 6 9
18–21
LVEF measurement
No H if symptoms or LVEF ↓ >15% or ↓ to <LLN
Pre-AC
Post-AC
LVEF=left ventricular ejection fraction; LLN=lower limit of normal

50. Impact of Joint Analysis on N9831 April 2005
Joint analysis with B-31: Concurrent approach
DMC asked for an unplanned interim analysis comparing Arm B (sequential) vs Arm C (concurrent) to assist in patient management
AC  T + H  H significantly improves disease-free and overall survival vs control: AC  T
DMC=data monitoring committee

51. Patient/Event Status at Time of Joint Analysis April 2005
Patients
Enrollment goals met (n: >3300)
700 patients on chemotherapy
2701 patients entered prior to 1/1/2005
Median follow up: 1.5 years
Total disease-free survival events
A and B: 220 (of 789 needed)
B and C: 147 (of 590 needed)

52. Results Disease-Free Survival
Joint Analysis
*Stratified – nodal status and receptor status
N9831 Analysis A B B C
*Stratified – nodal status and receptor status
**for patients randomized before 1/1/2005

53. Disease-Free Survival: A vs B N9831
100 90 80 70 60 50 40 30 20 10
AC → T → H Events=103
AC → T Events=117 %
Hazard ratio=0.87
Stratified logrank 2P=0.2936
Years
Number of patients followed A B

54. Disease-Free Survival: B vs C N9831
AC → T + H → H Events=53
100 90 80 70 60 50 40 30 20 10
AC → T → H Events=84 %
Hazard ratio=0.64
Stratified logrank 2P=0.0114
Years
Number of patients followed B C

55. Joint Analysis Results
Overall Survival
Joint Analysis Results
*Stratified – nodal status and receptor status
N9831 Analysis Results A B B C
*Stratified – nodal status and receptor status

56. Other Relevant Factors for Patient Management
HER2 testing
Cardiac tolerability comparisons based on planned analyses

57. HER2 Testing in N9831
Modest level of concordance between local and central laboratories for both IHC and FISH
With HercepTest™: 81% (78-83%)
With FISH: % (84-90%)
High level of agreement between central and reference laboratory results for HER2
94.5% for IHC (0, 1+, 2+)
95.1% for FISH (not amplified)
Accurate HER2 testing is critical given the degree of trastuzumab benefit as a component of adjuvant therapy
Conclusions: There was high level of discordance by either IHC or FISH between local and central laboratories: 20% for protein analysis when Herceptest was used locally, and 15% with FISH. When the discordant cases were retested there was a high level of agreement between central and the independent reference laboratory – for both IHC and FISH.
Updated from Perez EA, et al. ASCO 2004 (abstract 567)

58. Cardiac Monitoring Plan
Monthly formal review of LVEF, clinical data
Interim analyses after 100, 300, and 500 patients per arm
completed AC and followed at least 6 months
~ 9 months from registration
Perez EA, et al. ASCO 2005 (abstract 556)

59. Effect of the Introduction of H on Cardiac Tolerability
Difference in the incidence of cardiac events (CHF and cardiac deaths) between non-H and H arms is <4%
9 month analysis; 500 per arm with nl LVEF or LVEF decrease  15% from baseline (after AC)
0.0% (95% CI, %) for control
2.2% (95% CI, %) for control vs sequential
3.3% (95% CI, %) for control vs concurrent* therapy with paclitaxel
* at month 9, concurrent pts have received 3 additional months of H compared to sequential
Perez EA, et al. ASCO 2005 (abstract 556)

60. Effect of Introduction of H on Disease Recurrence Conclusions
52% decreased recurrence with concurrent vs control treatment (P=3X10-12) (joint analysis finding)
13% decreased recurrence with sequential vs control treatment (P=0.2936)
36% decreased recurrence with concurrent vs sequential treatment (P=0.0114)
More follow up is needed to determine whether this trend continues

61. NCCTG N9831 Next Steps
Pre-specified interim analyses at 50%, 67%, and 75% of events still planned
Continued exploration of predictive factors for cardiac toxicity
Continued patient follow up

62. FIRST RESULTS OF THE HERA TRIAL
ASCO, Scientific Session, May 16, 2005
FIRST RESULTS OF THE HERA TRIAL
A randomized three-arm multi-centre comparison of:
1 year Herceptin®
2 years Herceptin®
or no Herceptin®
in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy
Martine J. Piccart-Gebhart, MD, PhD on behalf of:
The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann – La Roche Ltd.

63. ACCRUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005)
NORDIC COUNTRIES
EASTERN EUROPE:
 11%
CANADA
71.5% EU
JAPAN
 12%
ASIA PACIFIC
CENTRAL &
SOUTH AMERICA
5.5%
AUSTRALIA – NEW ZEALAND
SOUTH AFRICA

64. HERA TRIAL DESIGN Women with HER2 POSITIVE invasive
breast cancer IHC3+ or FISH+ centrally confirmed
Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy
Stratification
Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region
Randomization
Trastuzumab
8 mg/kg  6 mg/kg
3 weekly x 2 years
Trastuzumab
8 mg/kg  6 mg/kg
3 weekly x 1 year
Observation

65. KEY INCLUSION CRITERIA
Centrally confirmed HER-2 overexpression or amplification
Node-positive or (sentinel) node-negative with  T1c
Completed  4 cycles of approved (neo)adjuvant chemotherapy regimen
Baseline LVEF  55% (Echo or MUGA)
Known hormone receptor status

66. ENDPOINTS AND ANALYSIS PLAN
Target accrual: 4482
HR = 0.77 (power 80% 2 sided  = 0.025)
for each pairwise test (1y vs nil or 2y vs nil)
SAFETY
EFFICACY
Tolerability
Incidence of cardiac dysfunction.
Primary endpoint: DFS
Secondary endpoints: RFS, DDFS, OS, 2 years vs 1 year trastuzumab
Three interim analysis of cardiac endpoints after n = 300 n = 600 n = 900 pts
Stopping rule:  4% absolute increase in primary cardiac events
One interim efficacy analysis (n = 475 events)
One primary core analysis (n = 951 events)

67. HERA FLOW CHART 5090 Women enrolled 5081 with available data
1 year median follow-up
Efficacy Analysis
N=3387
2y trastuzumab
N=1694
1y trastuzumab
N=1694
Observation
N=1693
N=20
N=3
N=26
Safety Analysis
N=3413
N= 1677
1y trastuzumab
N=1736
Observation

68. PATIENT/TUMOR CHARACTERISTICS
Age (%)
Observation (n = 1693)
1 year trastuzumab (n = 1694)
7.3
7.6
< 35 y y y
 60 y
missing
43.7
44.3
32.7
31.8
16.2
16.2
0.2
0.2
Adjuvant chemotherapy (%)
6.1
6.2
68.3
67.9
25.5
26.0
No anthracyclines,
no taxane
Anthracyclines
missing
0.1
0.2
Anthracyclines + taxanes

69. PATIENT/TUMOR CHARACTERISTICS
Menopausal status at randomization (%)
Observation (N=1693)
1 year trastuzumab (N=1694)
15.4
Prem
16.1
37.2
Uncertain
37.9
47.1
Postmenopausal
50.0

70. PATIENT/TUMOR CHARACTERISTICS
Observation (N=1693)
1 year trastuzumab (N=1694)
Nodal Status (%)
Any (neoadjuvant)
10.2
11.1
Node neg.
32.9
32.1
1-3 + nodes
28.9
28.5
 4 + nodes
27.9
28.3
missing
0.1
0.2
Hormone Receptor (%)
HR negative
49.9
49.0
49.0
HR positive
50.0
50.9

71. ADJUVANT ENDOCRINE THERAPY
Observation
1 year trastuzumab
TAM
64% AI
TAMAI 9%
11%
LHRH ± TAM
16%
TAM
66% 8%
17% AI
TAMAI
LHRH ± TAM

72. OVERVIEW OF ADVERSE EVENTS
Observation
(N=1736)
1 year trastuzumab
(N=1677) N % N %
Patients with at least one grade 3 or 4 AE 75
4.3
132
7.9
Patients with at least one SAE 81
4.7
117
7.0
3 (a)
6 (b)
Fatal AE
Treatment withdrawals
143 (c)
8.5
Cardiac failure, suicide, unknown
Cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis, two unknown
Reason: safety in 6%, refusal in 2.5%

73. SAFETY ANALYSIS POPULATION
Cardiotoxicity
Observation
N=1736
1 year trastuzumab
N=1677
Decrease by  10 EF points and LVEF < 50%
2.2 %
7.1 %
0 %
(95% CI: )
0.5%
(95% CI: )
Same LVEF criteria
and symptomatic CHF NYHA class III/IV, confirmed by cardiologist
Cardiac death
0.1% 0%

74. DISEASE-FREE SURVIVAL
% alive and disease free

75. DISEASE-FREE SURVIVAL Type of First Event
Observation
n= 220 events
1 year trastuzumab
n= 127 events
Distant event
70%
n=154
n= %
Loco regional event
23% n=50
n= %
3% n=7
n=6 5%
Contralateral breast Ca
3% n=6
n=3 2%
Second non breast malignancy
Death as first event
1% n=3
n=6 5%

76. DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation
Hazard
Hazard
ratio
ratio n n
All
All
3387
3387
0.54
0.54
Nodal
Nodal
status
status
Any, neo
Any, neo - -
adjuvant chemotherapy
adjuvant chemotherapy
358
358
0.53
0.53
0 pos, no neo
0 pos, no neo - -
adjuvant chemotherapy
adjuvant chemotherapy
1100
1100
0.52
0.52 1 1 - -
3 pos, no neo
3 pos, no neo - -
adjuvant chemotherapy
adjuvant chemotherapy
972
972
0.51
0.51
4 pos, no neo
4 pos, no neo - -
adjuvant chemotherapy
adjuvant chemotherapy
953
953
0.53
0.53
Adjuvant chemotherapy regimen
Adjuvant chemotherapy regimen
No anthracycline or taxane
No anthracycline or taxane
203
203
0.64
0.64
Anthracycline, no taxane
Anthracycline, no taxane
2307
2307
0.43
0.43
Anthracycline + taxane
Anthracycline + taxane
872
872
0.77
0.77
Receptor status/endocrine therapy
Receptor status/endocrine therapy
Negative
Negative
1674
1674
0.51
0.51
Pos + no endocrine therapy
Pos + no endocrine therapy
467
467
0.49
0.49
Pos + endocrine therapy
Pos + endocrine therapy
1234
1234
0.68
0.68
Age group
Age group
<35 yrs
<35 yrs
251
251
0.47
0.47 35 35 - -
49 yrs
49 yrs
1490
1490
0.52
0.52 50 50 - -
59 yrs
59 yrs
1091
1091
0.53
0.53
60 yrs
60 yrs
549
549
0.70
0.70
Region
Region
Europe, Nordic, Canada, SA, Aus, NZ
Europe, Nordic, Canada, SA, Aus, NZ
2430
2430
0.58
0.58
Asia Pacific, Japan
Asia Pacific, Japan
405
405
0.42
0.42
Eastern Europe
Eastern Europe
364
364
0.31
0.31
Central + South America
Central + South America
188
188
0.90
0.90
Favors
Favors 1 1
Favors
Favors 2 2
trastuzumab
trastuzumab
observation
observation

77. SECONDARY EFFICACY ENDPOINTS Intent-to-treat Analysis
RFS
DDFS OS
0.50
0.51
0.76
No of events
209
113
179 98 37 29
95% CI
p value (logrank)
2y outcome (%)
<
78.6 vs 87.2
<
81.8 vs 89.7
<0.26
95.0 vs 96.0
Observation
1 year trastuzumab

78. CONCLUSIONS At one year median follow-up:
Trastuzumab given every 3 weeks for one year following adjuvant chemotherapy significantly prolongs DFS and RFS for women with HER-2 positive early breast cancer
Trastuzumab significantly reduces the risk of distant metastases
Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics (nodal status, hormone receptor status, ...) and of type of adjuvant chemotherapy received

79. CONCLUSIONS
Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure; longer follow-up is needed to better quantify this risk
All patients continue to be followed for long-term safety: patients in the observation arm will be offered trastuzumab (guidelines in preparation)
Results regarding optimal trastuzumab duration (1 versus 2 years) should be available by 2008

80. HERA Study Design Elements
Randomized following ctx
DFS was primary endpoint
Most patients did not receive taxane
In contrast to the Joint analysis, HERA included a large percentage of node negative pts(About 1/3).
Very short median follow-up

81. Adjuvant Trastuzumab Summary and Conclusions
Does adjuvant trastuzumab improve DFS? YES!
Should we give trastuzumab with or following CTX?
What is the appropraite duration of trastuzumab?
What is the price of trastuzumab?

82. Should we give Trastuzumab before or after CTX?
Preclinical data suggest that trastuzumab may amplify ctx’s pro-apoptotic effects.
Synergistic activity in preclinical models for some ctx
Cardiotoxicity concerns when trastuzumab is given in proximity to anthracyclines.

83. What is the appropriate duration of Trastuzumab?
Unknown (HERA 1 vs. 2 yr pending)
Current data supports one year of therapy
Current data supports initiation of therapy for up to 6 months following completion of chemotherapy or radiation therapy
Could we get by with less trastuzumab?
( ie. only with chemo?)

84. What is the price of Trastuzumab?
Cardiac Toxicity(CHF) can be consequence of using trastuzumab
Rate = % AC-TH vs % AC-T (B31/ N9831)
Rate = % post ctx (HERA/N9831)
Degree of reversibility uncertain and requires further follow-up
Long term effects unknown
While benefit far outweighs the risks, the price is real and should be discussed with patients

85. Adjuvant Breast Cancer Node Positive and High Risk Node Negative
BCIRG 006
Adjuvant Breast Cancer
Node Positive and High Risk Node Negative
4 x AC 60/600 mg/m2
4 x Docetaxel
100 mg/m2
ACT
HER2 +
FISH
ACTH
1 Year Trastuzumab
N=3150
480 centres
6 x Docetaxel and Platinum salts
75 mg/m mg/m2 or AUC 6
TCH
1 Year Trastuzumab

86. BCIRG 006 LVEF Decline by NYHA Class
AC-T AC-TH TCH
>10 < LLN
>15%< LLN
Grade 3-4 CHF
Implication: Trastuzumab by itself is not cardiotoxic; it becomes so when it keeps company with doxorubicin.

87. Intergroup Guidelines for N9831
For women receiving trastuzumab, continue until 1 year is completed.
For women randomized to 1 yr TH, continue as planned
For women on Arm A: AC-T and are at most 6 months from completion of paclitaxel, begin weekly trastuzumab and continue until you have completed 1 yr of trastuzumab with cardiac testing.

88. Intergroup Guidelines for N9831
For women on Arm A: AC-T and have not started paclitaxel, begin weekly trastuzumab with paclitaxel and continue until 1 yr of trastuzumab is completed, with cardiac testing.
For women on Arm B: AC-T-H, and you have not begun trastuzumab, begin trastuzumab with paclitaxel and continue for 1 yr. with cardiac testing.
If ctx completed > 6 mo. and have not received trastuzumab, discuss risks and benefits.

90. E2100 A Randomized Phase III Trial of Paclitaxel versus Paclitaxel plus Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer
KD Miller, M Wang, J Gralow, M Dickler, MA Cobleigh, EA Perez, TN Shenkier, NE Davidson
Indiana University Cancer Center, Dana Farber Cancer Institute, Pudget Sound Oncology Consortium, Memorial Sloan Kettering Cancer Center, Rush-Presbyterian-St. Luke’s Medical Center, Mayo Clinic, British Columbia Cancer Agency, Vancouver Cancer Center, Johns Hopkins Oncology Center

91. Rationale Tumor growth is dependent on angiogenesis
Bevacizumab is a humanized monoclonal antibody directed against VEGF
Recognizes all VEGF-A isoforms
Active in patients with refractory MBC
9% response rate as monotherapy
Increases ORR but not PFS in combination with capecitabine
Greater activity expected in less heavily pre-treated patients

92. Study Design Stratify: DFI < 24 mos. vs. > 24 mos.
< 3 vs. > 3 metastatic sites
Adjuvant chemotherapy yes vs. no
ER+ vs. ER- vs. ER unknown
RANDOMI ZE
Paclitaxel + Bevacizumab
Paclitaxel
28-day cycle:
Paclitaxel 90 mg/m2 D1, 8 and 15
Bevacizumab 10 mg/kg D1 and 15

93. Key Eligibility Criteria
Locally recurrent or metastatic breast cancer
HER2+ only if prior treatment with trastuzumab or contraindication
No prior chemo regimens for MBC
Adjuvant taxane allowed if DFI > 12 months
ECOG PS 0 or 1
No anti-tumor therapy within 21 days
No CNS mets (head CT or MR required)
No significant proteinuria (> 500 mg/24 hr)
No therapeutic anticoagulation

94. Statistical Design - Efficacy
Primary endpoint: Progression-Free Survival
85% power for a 33% improvement
6 vs. 8 months
One-sided type I error  2.5%
Requires 650 eligible patients
Final analysis after 546 PFS events
Interim analyses after 270 and 425 events
Asymmetric boundaries to stop early either for demonstrated benefit or for lack of benefit
O-Brien-Fleming boundaries and repeated confidence interval analyses at each interim

95. Statistical Design - Safety
Type I event: Grade 4 hemorrhage or HTN
Acceptable rate: 1%
Type II event: Grade 3/4 thrombosis or embolism
Acceptable rate: 5%

96. Current Analysis Study activated Dec 21, 2001 Closed March 24, 2004
715 eligible patients
First planned interim analysis
Data cut-off February 9, 2005
355 events
Progression – 291
Death without documented progression - 64

97. Patient Characteristics
Paclitaxel
(n=350)
Pac. + Bev.
(n=365)
Treated
346
365
Median age
55 (27-85)
56 (29-84)
DFI < 24 months
41%
> 3 sites
29%
28%
Adjuvant chemo.
64%
65%
ER+
63%

98. Response P<0.0001 P<0.0001 34.3% 28.2% 16.4% 14.2% 316 330 250
236

99. Progression Free Survival
HR = ( )
Log Rank Test p<0.001
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PFS Proportion 10 20 30
Pac. + Bev months
Paclitaxel months

100. Overall Survival OS Proportion Months Pac. + Bev. Paclitaxel
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 10 20 30 40
Months
OS Proportion
Pac. + Bev.
Paclitaxel
HR = ( )
Log Rank Test p=0.01

101. Bevacizumab Toxicity NCI-CTC Grade 3 and 4
Paclitaxel
(n=330)
Pac. + Bev.
(n=342) %
Grade 3
Grade 4
HTN* 13
0.3
Thromboembolic
0.9
1.2
Bleeding
0.6
Proteinuria**
1.5
*p<0.0001; **p=0.0004
NCI-CTC v3.0, worst per patient

102. Other Toxicities NCI-CTC Grade 3 and 4
Paclitaxel
(n=330)
Pac. + Bev.
(n=342) %
Grade 3
Grade 4
Neuropathy*
13.6
0.6
19.9
Fatigue
2.7
4.7
0.3
Neutropenia 3
0.9
4.4
 LVEF
*p=0.01
NCI-CTC v3.0, worst per patient

103. Ongoing Correlative Studies
Quality of Life (FACT-B)
Circulating markers
Serum VCAM-1
Urine VEGF
Analysis of primary tumor samples
VEGF expression

104. Conclusions and Future Directions
Addition of bevacizumab to paclitaxel
Significantly prolongs progression free survival
Increases objective response rate
Longer follow-up required to assess impact on OS
Further studies should
Explore the role of Bevacizumab in the adjuvant setting
Develop methods to identify patients who are most likely to benefit from VEGF-targeted therapies

105. Adjuvant Pilot Trial Rationale
Most successful use of anti-angiogenic therapy predicted to be in adjuvant setting
Require large trial for proof of concept
Limitations of metastatic trials
Chronic therapy in only a few patients
Different tolerance for toxicity
Different metabolism (?)
Less concern for rare but potentially fatal toxicities

106. E2104 Schema Arm A: ddBAC >BT >B Arm B: ddAC >BT >B R E GI S T
Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2
Bevacizumab 10 mg/kg
every 14 days x 4
Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4
Bevacizumab 10 mg/kg every 14 days x 18
Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2
every 14 days x 4
Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4
Bevacizumab 10 mg/kg every 14 days x 22
Arm B: ddAC >BT >B
*Hormone therapy and radiation per standard care